Type I diabetes is caused by selective destruction of the insulin-producing islet cells in the pancreas. This destruction is mediated by autoreactive T cells and correlates with the migration of a sub-population of IFN gamma-producing cells to the site of tissue damage. The specific aim of this Phase I proposal is to test the possibility that disease induction in NOD mice may be preventable by blocking the migration of IFN gamma-producing cells into the pancreas. Their approach will focus on two chemokines, MIP-1 alpha and MCP-1, which appear to regulated migration of disease-associated IFN gamma-secreting T cells in other disease models. Using a system which distinguishes between destructive and non-destructive autoimmunity in NOD mice, they will test whether expression of the chemokines MIP-1 alpha and MCP-1 correlates with the appearance of either destructive or non- destructive autoimmunity in this model. They will also test whether neutralizing antibodies specific for either of these chemokines will inhibit the generation of either destructive or non-destructive autoimmunity in NOD mice. The long-term goal of this project beyond this phase I study is to develop a low molecular weight antagonist to the chemokine which regulates the migration of IFN gamma-producing cells into the pancreas of disease-susceptible hosts and evaluate this antagonist as a potential novel mode of therapeutic intervention first in NOD mice and then humans. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE